The objective of this proposal is to exploit two enzymatic differences between normal cells and some cancers in the design of specific tumor targeted chemotherapy. The first metabolic difference concerns methylthioadenosine phosphorylase (MTAase), an enzyme important in purine and polyamine metabolism. We have found that some human cancers, but not normal cells, are completely deficient in MTAase. Moreover, we have devised a method using MTA in combination with azaserine or high dose methotrexate for the selective killing of enzyme deficient cell that spares normal cells. The second metabolic difference concerns deoxycytidine kinase, an enzyme with low activity in most normal cells of non-lymphoid origin, but with increased activity in some tumors. We have studied a novel anti-metabolite, 2-chlorodeosyadenosine (CdA) that requires deoxycytidine kinase for activation, is markedly effective in L1210 leukemia, but whose toxicity is cell cycle independent. We now plan to assay levels of MTAase and deoxycytidine kinase in multiple human tumor specimens, and to measure the in vitro sensitivity of cancer cell of varying phenotype to MTA, in combination with azaserine or methotrexate, and to CdA. Finally, when Phase I studies are complete, we plan to test the therapeutic efficacy of each regimen in human malignancies with the appropriate enzyme profile. In this way, we plan to exploit a natural enzyme deficiency that is present in some human tumor cells but not in normal cells, and a new deoxynucleoside anit-metabolite that is cell cycle non-specific, but is activated by deoxycytidine kinase, in the clinical implementation of novel cancer chemotherapeutic regimens, grounded in rational, predictive in vitro tests.